This invention relates to certain substituted N-methylene derivatives of thienamycin sulfoxide (I, n=1) and sulfone (I, n=2): ##STR2## wherein X and Y are selected from the group consisting of hydrogen, R, OR, SR, and NR.sup.1 R.sup.2 wherein, inter alia, R is substituted or unsubstituted: alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, and heterocyclylalkyl; R.sup.1 and R.sup.2 are hydrogen or R. Such compounds and their pharmaceutically acceptable salt, ether, ester, and amide derivatives are useful as antibiotics. This invention also relates to processes for the preparation of such compounds; pharmaceutical compositions comprising such compounds; and methods of treatment comprising administering such compounds and compositions when an antibiotic effect is indicated.
Thienamycin is disclosed and claimed in U.S. Pat. No. 3,950,357 issued Apr. 13, 1976; said application is incorporated herein by reference since thienamycin may serve as the starting material in the preparation of the compounds of the present invention. Thienamycin is known to have the following structural formula (Ia): ##STR3##
Thienamycin and all of its isomers (in pure form and as mixtures) are also obtainable by the total synthesis disclosed and claimed in co-pending, commonly assigned U.S. patent application Ser. No. 792,071 (filed Apr. 28, 1977), now abandoned in favor of Continuation-in-part application Ser. No. 833,210, filed Sept. 15, 1977 now abandoned. This application is incorporated herein by reference to the extent that it makes available all isomers of Ia as starting materials in the preparation of the compounds of the present invention. Additionally incorporated by reference is co-pending commonly assigned U.S. patent application Ser. No. 734,584 filed Oct. 21, 1976 now abandoned, which discloses and claims two distinct isomeric forms of Ia which are antibiotics and which are isolated, as N-acetyl derivatives, as natural product of fermentation. Also incorporated by reference are U.S. patent applications Ser. No. 821,679 filed Aug. 4, 1977 now abandoned and its continuation-in-part, filed concurrently with the present application [Merck & Co., Inc. Attorney's Docket Number 15867IA] now U.S. Ser. No. 833,620, filed Sept. 15, 1977, U.S. Pat. No. 4,123,547; and 733,654 filed Oct. 18, 1976, now abandoned in favor of Continuation-in-part application U.S. Ser. No. 852,425, filed Nov. 17, 1977 which disclose and claim, respectively, thienamycin sulfoxide and thienamycin sulfone (Ib) and N-substituted methylene derivatives of thienamycin (1): ##STR4## wherein relative to 1, X, Y, X', R.sup.3' and R.sup.3 are the same as defined below for the compounds of the present invention (I). These applications are incorporated herein by reference since the species of structure 1 are useful starting materials for the preparation of the compounds of the present invention, (I), when oxidized according to the procedure described in the application directed to the sulfoxide/sulfone species Ib.
The substituted N-methylene thienamycin S-oxide and dioxide derivatives of the present invention may be depicted, as above, by the following structural formula: ##STR5## which, depending upon the basicity of the amino nitrogen (a function of the identity of the methylene substituents X and Y), may equivalently be represented as an inner salt: ##STR6## which is one canonical form of a single resonant structure, which, for example, when Y is -NR.sup.1 R.sup.2 and X is R is: ##STR7## Relative to the compounds of the present invention I: n is 1 or 2; and X and Y are independently selected from the group consisting of hydrogen, -R, -OR, -SR, and -NR.sup.1 R.sup.2 ; R.sup.1 and R.sup.2 are independently selected from R, hydrogen, nitro, hydroxyl, alkoxyl having 1-6 carbon atoms, amino, mono- di- and trialkylamino wherein the alkyl moieties each comprise 1-6 carbon atoms; R.sup.1 and R.sup.2 may be joined together to form a substituted or unsubstituted mono- or bicyclic heteroaryl or heterocyclyl comprising (together with the nitrogen atom to which they are attached) 4-10 atoms one or more of which may be an additional hetero atom selected from oxygen sulphur or nitrogen; R, R.sup.1 and R.sup.2 are substituted or unsubstituted: cyano; carbamoyl; carboxyl; alkoxycarbonyl and alkyl having from 1 to about 10 carbon atoms; alkynyl having from 2 to 10 carbon atoms; cycloalkyl having from 3 to 10 carbon atoms; cycloalkylalkyl and cycloalkylalklenyl having from 4 to 12 carbon atoms; cycloalkenyl, cycloalkenylalkenyl, and cycloalkenylalkyl having 3-10, 4-12 and 4-12 carbon atoms, respectively; aryl having from 6 to 10 carbon atoms, aralkyl, aralkenyl, and aralkynyl having from 7 to 16 carbon atoms; mono- and bicyclic heteroaryl and heteroaralkyl which typically comprise 4 to 10 ring atoms one or more of which is a hetero atom selected from oxygen, sulphur, or nitrogen and wherein the alkyl moiety of the heteroaralkyl radical comprises 1 to about 6 carbon atoms; mono- and bicyclic heterocyclyl and heterocyclylalkyl which typically comprises 4 to 10 ring atoms one or more of which is a hetero atom selected from oxygen, sulphur or nitrogen and wherein the alkyl moiety of the heterocyclylalkyl radical comprises from 1 to about 6 carbon atoms; and wherein the above-mentioned substituent or substituents on R, R.sup.1, R.sup.2 or on the ring formed by the joinder of R.sup.1 and R.sup.2, are selected from the group consisting of: halo, such as chloro, bromo, iodo and fluoro; azido; alkyl having 1-4 carbon atoms; thio; sulpho; phosphono; cyanothio (-SCN); nitro; cyano; amino; hydrazino; mono-, di- and trialkyl substituted amino, and hydrazino wherein the alkyl has 1-6 carbon atoms; hydroxyl; alkoxyl having 1-6 carbon atoms; alkylthio having 1-6 carbon atoms; carboxyl; oxo; alkoxylcarbonyl having 1-6 carbon atoms in the alkoxyl moiety; acyloxy comprising 2-10 carbon atoms; carbamoyl and mono- and dialkylcarbamoyl wherein the alkyl groups have 1-4 carbon atoms.
The compounds of the present invention also embrace embodiments of the following structure: ##STR8## which may also exist as salts: ##STR9## wherein the non-critical counter anion, A, is representatively selected to provide pharmaceutically acceptable salts such as halides (chloro, bromo and the like), sulfate, phosphate, citrate, acetate, benzoate and the like; and R.sup.3, X' and R.sup.3' are independently selected from the groups hereinafter defined: X' is oxygen, sulphur or NR' (R' is hydrogen or R.sup.3'); R.sup.3' is hydrogen, or, inter alia, is representatively selected to provide the pharmaceutically acceptable salt, ester, anhydride (R.sup.3' is acyl), and amide moieties known in the bicyclic .beta.-lactam antibiotic art-such moieties are enumerated in greater detail below; and R.sup.3 is: 1.) acyl (generically the group OR.sup.3 is classifiable as an ester); or 2.) R.sup.3 is selected from alkyl, aryl, alkenyl, aralkyl and the like (such that the group OR.sup.3 is generically classifiable as an ether). R.sup.3 may also be hydrogen. The term "acyl" is by definition inclusive of the alkanoyls including derivatives and analogues thereof such as thio analogues wherein the carbonyl oxygen is replaced by sulphur; as well as sulphur and phosphorous acyl analogues such as substituted sulfonyl-, sulfinyl-, and sulfenyl radicals, and substituted P(III and V) radicals such as substituted phosphorous-, phosphoric-, phosphonous- and phosphonic radicals. Such radicals, R.sup.3, of the present invention are enumerated in greater detail below.
There is a continuing need for new antibiotics. For unfortunately, there is no static effectiveness of a given antibiotic because continued wide scale usage of any such antibiotic selectively gives rise to resistant strains of pathogens. In addition, the known antibiotics suffer from the disadvantage of being effective only against certain types of microorganisms. Accordingly, the search for new antibiotics continues.
Unexpectedly, it has been found that the compounds of the present invention are broad spectrum antibiotics, which are useful in animal and human therapy and in inanimate systems.
Thus, it is an object of the present invention to provide a novel class of antibiotics which possess the basic nuclear structure of thienamycin (Ia), but which are characterized as sulfoxide/sulfone substituted N-methylene derivatives thereof. These antibiotics are active against a broad range of pathogens which representatively include both gram positive bacteria such as S. aureus, Strep. pyogenes, and B. subtilis and gram negative bacteria such as E. coli, Proteus morganii, Klebsiella, Serratia and Pseudomonas. Further objects of this invention are to provide chemical processes for the preparation of such antibiotics and their non-toxic pharmaceutically acceptable salt, ether, ester and amide derivatives; pharmaceutical compositions comrpising such antibiotics; and to provide methods of treatment comprising administering such antibiotics and compositions when an antibiotic effect is indicated.